CN110856719B - Medicinal composition of 2-aminopyrimidine compounds - Google Patents
Medicinal composition of 2-aminopyrimidine compounds Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a medicinal composition of a 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof. In particular, the present invention provides a pharmaceutical composition comprising N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide, or a pharmaceutically acceptable salt thereof, and a process for preparing the pharmaceutical composition.
Description
Technical Field
The present invention is in the field of pharmaceutical formulations, and in particular, relates to a pharmaceutical composition of the compound N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide, or a pharmaceutically acceptable salt thereof, and a process for preparing the pharmaceutical composition.
Background
Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine protein kinase, regulates cell proliferation, survival, adhesion, migration and differentiation. EGFR is over-activated or persistently activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer, and the like. Blocking the activation of EGFR and Erb-B2 has been clinically validated as the leading approach to target treatment of tumor cells. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, have received rapid FDA approval in the united states for the treatment of advanced non-small cell lung cancer (NSCLC) patients who have lost response to conventional chemotherapy.
The response rate of NSCLC patients positive to EGFR activating mutation to EGFR-TKI (EGFR-tyrosine kinase inhibitor) is significantly higher than that of EGFR wild type NSCLC patients, and the Progression Free Survival (PFS) phase and the total survival (OS) phase are also significantly prolonged. However, most patients positive for EGFR mutations have no more than 12-14 months of PFS, i.e., resistance to TKI. The mechanism of acquired drug resistance and its clinical coping strategy become another research hotspot in the field of targeted therapy.
N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide has a chemical structure shown in formula I. The compound shown in the formula I is an EGFR inhibitor for selectively inhibiting EGFRT790M mutation, can overcome drug resistance induced by the existing drugs of gefitinib, erlotinib and the like, and has weak inhibitory activity on wild type EGFR. However, there is a lack in the art of pharmaceutical compositions that accommodate administration of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide.
The unpublished Chinese patent application CN201710108703.X describes a pharmaceutical composition of the compound of formula I; the unpublished Chinese patent application CN201810332187.3 describes pharmaceutically acceptable salts of the compounds of formula I.
Disclosure of Invention
It is an object of the present invention to provide a pharmaceutical composition suitable for the administration of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide, or a pharmaceutically acceptable salt thereof.
In a first aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, said pharmaceutical composition comprising an active ingredient, a filler, a lubricant, and a disintegrant, prepared via a powder direct compression process;
the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;
the disintegrant is crospovidone.
The pharmaceutical composition can also contain glidants; the glidant is preferably talc or colloidal silicon dioxide. In a preferred embodiment, the weight ratio of the glidant to the active ingredient is 0.005:1 to 0.2:1, preferably 0.01:1 to 0.1: 1.
The filler is selected from the group consisting of: starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, dibasic calcium phosphate, sorbitol, mannitol, or a combination thereof.
In a preferred embodiment, the filler is a combination of a first filler and a second filler, the first filler is mannitol and/or lactose, and the second filler is microcrystalline cellulose.
In a preferred embodiment, the weight ratio of the first filler to the second filler is preferably 9:1 to 1:9, and more preferably 9:1 to 1: 3.
In a preferred embodiment, the weight ratio of the filler to the active ingredient is 99:1 to 1:9, preferably 8:1 to 1:1, more preferably 4:1 to 2: 1.
The lubricant is selected from the group consisting of: magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, or combinations thereof; sodium stearyl fumarate is preferred.
In a preferred embodiment, the weight ratio of the lubricant to the active ingredient is 1:1 to 1:200, preferably 1:2 to 1:50, more preferably 1:5 to 1: 15.
In a preferred embodiment, the weight ratio of the disintegrant to the active ingredient is 1:1 to 1:90, preferably 1:1 to 1:30, more preferably 1:2 to 1: 15.
In a preferred embodiment, the pharmaceutical composition is for use in the preparation of a medicament for treating a cancer in a patient, preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
In a preferred embodiment, the pharmaceutical composition is for use in treating cancer in a patient, preferably the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, said pharmaceutical composition comprising an active ingredient, a filler, a lubricant, and a disintegrant, prepared via a powder direct compression process;
the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;
the pharmaceutical composition is free of colloidal silica.
The filler is selected from the group consisting of: starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, dibasic calcium phosphate, sorbitol, mannitol, or a combination thereof.
In a preferred embodiment, the filler is a combination of a first filler and a second filler, the first filler is mannitol and/or lactose, and the second filler is microcrystalline cellulose.
In a preferred embodiment, the weight ratio of the first filler to the second filler is preferably 9:1 to 1:9, and more preferably 9:1 to 1: 3.
In a preferred embodiment, the weight ratio of the filler to the active ingredient is 99:1 to 1:9, preferably 8:1 to 1:1, more preferably 4:1 to 2: 1.
The lubricant is selected from the group consisting of: magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, or combinations thereof; sodium stearyl fumarate is preferred.
In a preferred embodiment, the weight ratio of the lubricant to the active ingredient is 1:1 to 1:200, preferably 1:2 to 1:50, more preferably 1:5 to 1: 15.
The disintegrant is crospovidone, low-substituted hydroxypropyl cellulose, or a combination thereof.
In a preferred embodiment, the weight ratio of the disintegrant to the active ingredient is 1:1 to 1:90, preferably 1:1 to 1:30, more preferably 1:2 to 1: 15.
In a preferred embodiment, the pharmaceutical composition is for use in the preparation of a medicament for treating a cancer in a patient, preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
In a preferred embodiment, the pharmaceutical composition is for use in treating cancer in a patient, preferably the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
In a third aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition according to the first or second aspect of the present invention, said process comprising: (1) mixing active ingredient, filler, lubricant, and disintegrant to obtain intermediate powder; (2) tabletting was performed according to tablet weight.
When the pharmaceutical composition contains the glidant, the preparation method comprises the following steps: (1) uniformly mixing the active ingredients, the filling agent, the lubricant, the disintegrant and the glidant to obtain intermediate powder; (2) tabletting was performed according to tablet weight.
In a preferred embodiment, the active ingredient is in powder form.
In a preferred embodiment, the active ingredient powder is obtained by mechanically pulverizing a bulk drug of a compound of formula I or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the active ingredient powder is obtained by sieving a drug substance of the compound I or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the active ingredient powder is obtained by mechanically pulverizing a bulk drug of the compound of formula I or a pharmaceutically acceptable salt thereof, and sieving the pulverized bulk drug.
In a fourth aspect of the invention, there is provided a pharmaceutical tablet comprising a pharmaceutical composition according to the first or second aspects of the invention.
In a preferred embodiment, the pharmaceutical tablet comprises a core and a coating covering the core, wherein the core is the pharmaceutical composition of the first aspect or the second aspect of the invention.
In a preferred embodiment, the pharmaceutical tablet is for use in the manufacture of a medicament for the treatment of cancer in a patient, preferably, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
In a preferred embodiment, the pharmaceutical tablet is for use in treating cancer in a patient, preferably the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a graph of the dissolution profiles of three batches of 10mg sized tablets in dissolution medium pH3.8 of comparative example 1;
FIG. 2 is a dissolution profile of three batches of 80mg sized tablets in dissolution medium pH3.8 of comparative example 1;
FIG. 3 is a graph of the dissolution profiles of tablets of group A, group B, group C, and group D of comparative example 3 in dissolution medium pH 3.8;
figure 4 is a dissolution profile of the tablets of examples 3 to 6 in dissolution medium ph 3.8.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time to provide a pharmaceutical composition suitable for the administration of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide, or a pharmaceutically acceptable salt thereof. The medicinal composition has excellent dissolution rate and chemical stability. Based on the above findings, the inventors have completed the present invention.
Term(s) for
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …" or "consisting of …".
As used herein, the term "… … -sized tablet core" or "… … -sized tablet" has the following meaning: each core or each tablet contains a quantity of a compound of formula I; for example, a 10mg sized tablet core represents about 10mg of a compound of formula I per tablet core. Pharmaceutically acceptable salts of the compounds of formula I are reduced according to the compounds of formula I.
Pharmaceutically acceptable salts of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide
The pharmaceutically acceptable salt of the compound I is an inorganic salt or an organic salt formed by the compound I and any acid. The salt may be selected from the group consisting of phosphate, hydrochloride, hydrobromide, sulphate, methanesulphonate, p-toluenesulphonate, fumarate, tartrate, citrate, succinate, adipate, maleate, lactate, malate, camphorsulphonate, nitrate, acetate and benzoate.
The acid comprises any optical isomer, raceme and meso form of the acid. For example, the tartaric acid can be L-tartaric acid, D-tartaric acid and DL-tartaric acid. The camphorsulfonic acid may be D-camphorsulfonic acid, L-camphorsulfonic acid, DL-camphorsulfonic acid, etc.
The phosphate salt of compound I is composed of compound I and phosphoric acid in a molar ratio of about 3:1, alternatively about 2:1, alternatively about 1: 1. The sulfate salt of compound I consists of compound I and sulfuric acid in a molar ratio of about 2:1, or about 1: 1. The hydrochloride, citrate, acetate, maleate, tartrate, fumarate, camphorsulfonate, methanesulfonate, malate, succinate, adipate, benzoate, hydrobromide, lactate and nitrate salts of compound I consist of compound I and the corresponding acid in a molar ratio of about 1: 1.
The process for preparing a pharmaceutically acceptable salt of compound I may be a salt-forming process conventional in the art, including a step of forming compound I into a salt with a corresponding acid.
Pharmaceutically acceptable salts of compound I, preferably the phosphate salt (e.g. compound I to phosphoric acid molar ratio of about 1:1, i.e. dihydrogen phosphate), the sulfate salt (e.g. compound I to sulfuric acid molar ratio of about 1:1, i.e. hydrogen sulfate), the hydrobromide or camphorsulfonate salt of compound I, more preferably the phosphate (e.g. dihydrogen phosphate) and the sulfate salt (e.g. hydrogen sulfate) of compound I.
Pharmaceutical compositions of N- ((5- ((5-chloro-4- ((naphthalen-2-yl) amino)) pyrimidin-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide drugs or pharmaceutically acceptable salts thereof
The invention aims to provide a pharmaceutical composition which is suitable for industrial production and meets the requirement of clinical use and is prepared from a compound N- ((5- ((5-chloro-4- ((naphthalene-2-yl) amino)) pyrimidine-2-yl) amino) -2- ((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutically acceptable salt thereof.
The inventor of the present invention has encountered a plurality of technical problems in the process of researching a pharmaceutical composition which is suitable for industrial production and meets the clinical use requirement of the compound of formula I or the pharmaceutically acceptable salt thereof. For example, (1) the poor flowability of the compound of formula I affects the content uniformity, the batch-to-batch dissolution consistency, etc. of the pharmaceutical composition; (2) the compound of the formula I is easy to oxidize, the required process is quick and simple, and the preparation time is shortened as much as possible; (3) for patients with non-small cell lung cancer, particularly for patients with advanced stage, dysphagia caused by respiratory system disorder requires that the medicine can be administered by nasal feeding and the like; (4) the dissolution rate is reduced after long-term storage.
As known to those skilled in the art, the tabletting method can be divided into two main categories, namely granulation and direct compression, according to the different tabletting process routes. Furthermore, the granulation and tabletting method can be divided into a wet granulation and tabletting method and a dry granulation and tabletting method, and the direct tabletting method can be divided into a direct powder tabletting method and a semi-dry granule tabletting method.
The direct compression method is a method of directly compressing a mixture of a drug and an auxiliary material without a granulation process. The direct tabletting method has the defects of poor powder flowability, poor content uniformity and large tablet weight difference; therefore, the requirement on the flowability of the raw material medicine is higher. The compound of formula I has poor flowability as a bulk drug, and the inventors' studies indicate that poor flowability is independent of the crystal structure of the bulk drug. For those skilled in the art, the powder direct compression method is not suitable for manufacturing pharmaceutical compositions suitable for industrial production of the compound of formula I and meeting the clinical requirement.
However, after numerous attempts to overcome the four subclasses of tableting methods, the inventors have surprisingly found that by the present invention, a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of a tablet with uniform content and stable tablet weight can be obtained by direct powder tableting, overcoming the disadvantage of poor flowability. More surprisingly, the pharmaceutical composition in the form of tablets prepared by the direct powder compression method provided by the invention has short disintegration time and high dissolution speed. It has also been found that good dissolution properties can still be ensured after long-term storage.
Therefore, the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, which is suitable for industrial production and meets the clinical use requirement; the pharmaceutical composition is preferably in the form of a tablet. The pharmaceutical composition is prepared by a powder direct compression method and consists of a compound shown in formula I or pharmaceutically acceptable salt thereof, a filling agent, a lubricating agent and a disintegrating agent.
The compound of formula I or a pharmaceutically acceptable salt thereof is present as the active ingredient in a pharmaceutical composition, and the amount thereof can generally be flexibly set depending on the requirements of the mode of administration.
The pharmaceutical composition of the present invention may select one, two, three or more fillers. Bulking agents, which may also be referred to as diluents, primarily serve to increase the weight and/or volume of the pharmaceutical composition; and can reduce dosage deviation of active ingredients and improve compression formability. Pharmaceutical fillers include, but are not limited to, one or more of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, dibasic calcium phosphate, sorbitol, mannitol.
In the present invention, the weight ratio of the filler to the active ingredient is 99:1 to 1:9, preferably 8:1 to 1:1, more preferably 4:1 to 2:1
In the present invention, the filler is preferably a combination of a first filler and a second filler, the first filler being mannitol and/or lactose, and the second filler being microcrystalline cellulose. Wherein the weight ratio of the first filler to the second filler is preferably 9:1 to 1:9, more preferably 9:1 to 1: 3.
Suitable microcrystalline cellulose has an average particle size of 20 to 200 μm, and is commercially available, for example, from FMC, Avicel PH-102, Avicel HFE-102, Avicel PH-301, Avicel PH-302, and Avicel PH-200.
The lubricant is added before tabletting to reduce the friction between the granules or tablets and a punching die, and the lubricant can reduce the friction with the punching die, increase the sliding property of the granules, ensure good filling and uniform density distribution of the tablets and ensure the integrity of the pushed tablets. The pharmaceutical composition of the present invention may select one, two, three or more lubricants. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate. Sodium stearyl fumarate is preferred as the lubricant of the present invention. In the invention, the weight ratio of the lubricant to the active ingredient is 1: 1-1: 200, preferably 1: 2-1: 50, and more preferably 1: 5-1: 15.
Disintegrants are excipients that facilitate rapid disintegration of tablets into fine particles in gastrointestinal fluids. Common pharmaceutical disintegrants include, but are not limited to, dry starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone. The present invention preferably uses low-substituted hydroxypropylcellulose and/or crospovidone as a disintegrant; more preferably, low substituted hydroxypropyl cellulose or crospovidone is used; even more preferably crospovidone is used. In the invention, the weight ratio of the disintegrant to the active ingredient is 1: 1-1: 90, preferably 1: 1-1: 30, and more preferably 1: 2-1: 15.
The particle size distribution of the raw material drug influences the dissolution rate of the tablet. In order to ensure the dissolution rate of the active ingredient, in the present invention, the particle diameter D90 of the active ingredient is preferably controlled to be 30 to 200 μm, and the particle diameter D90 of the active ingredient is more preferably controlled to be 30 to 120 μm. The present invention may employ means known in the art to control the particle size of the compound of formula I or a pharmaceutically acceptable salt thereof, preferably by subjecting the active ingredient to comminution and/or sieving means; more preferably, the active ingredient is processed by sieving with 80-200 mesh sieve (optionally, pulverizing before sieving).
The above pharmaceutical composition is prepared by a direct powder compression method comprising: (1) mixing active ingredient, filler, lubricant, and disintegrant to obtain intermediate powder; (2) tabletting was performed according to tablet weight. After the intermediate powder is prepared, the content can be detected, the tablet weight is calculated according to the content measurement result, and tabletting is carried out.
Pharmaceutical tablets and their preparation
The invention also provides a pharmaceutical tablet comprising a pharmaceutical composition as described above. Preferably, in the present invention, the absolute content of the compound of formula I or a pharmaceutically acceptable salt thereof in the tablet is 1-2000 mg/tablet, based on the weight of the tablet; more preferably, the absolute content is 10-500 mg/tablet, for example, the absolute content of the compound of formula I or a pharmaceutically acceptable salt thereof in a tablet can be 10 mg/tablet, 20 mg/tablet, 40 mg/tablet, 80 mg/tablet, 100 mg/tablet, 160 mg/tablet, 240 mg/tablet.
In one embodiment of the invention, there is provided a pharmaceutical tablet comprising a core comprising a pharmaceutical composition as described above, the core further having a coating.
Depending on the coating material, the coated tablets may be mainly classified into sugar-coated tablets, film-coated tablets, and enteric-coated tablets. In the present invention, the coating is a suitable coating, preferably a film coating, which is known not to negatively affect the dissolution of the final formulation. The tablet core can be provided with a sealing coating through a film coating, so that the patient and clinical personnel can be protected, the tablet core is prevented from contacting with air and moisture, and the chance of degradation of the medicine is reduced.
Suitable film coating materials include film formers, such as film forming polymers. Preferably, the film coating material further comprises additional components, such as plasticizers, colorants, dispersion aids and opacifiers. Plasticizers may be used to improve the film flexibility and durability and adhesion characteristics of the film coating. Preferred film-forming polymers are selected from one or more of film-forming vinyl polymers (e.g., polyvinyl alcohol), film-forming acrylic polymers (e.g., methacrylic acid-methyl methacrylate copolymer), esters of water-soluble cellulose ethers (e.g., hydroxypropyl methylcellulose phthalate), and the like. Suitable plasticizers include, for example, glycerol, acetylated monoglycerides, citric acid esters, propylene glycol, polyethylene glycol, triglycerides or phthalates. Suitable opacifying and coloring agents include, for example, titanium dioxide, iron sesquioxide. Suitable dispersion aids include, for example, talc.
The coating weight gain may be from 0.5% to 10%, preferably from 1% to 6%, more preferably from 2.5% to 5% by weight of the pharmaceutical composition. Suitable film coating materials may be concentrates, the coating being formulated with water or an organic solvent prior to spraying onto the core. Such concentrates include the Opadry (Opadry) series of coatings available from karaoke (Colorcon).
Use of pharmaceutical compositions
The invention also provides the use of the above pharmaceutical composition or tablet in the manufacture of a medicament for the treatment of cancer in a patient. The invention also provides the use of the above pharmaceutical composition or tablet for treating cancer in a patient. Preferably, the cancer is lung cancer, more preferably, the cancer is non-small cell lung cancer, and particularly preferably, the cancer is EGFR-positive mutant non-cell lung cancer. In one embodiment of the invention, the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
When the pharmaceutical composition is used, a safe and effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient (such as a human) in need of treatment, wherein the administration dose is a pharmaceutically considered effective administration dose, and the daily administration dose of the compound of formula I or the pharmaceutically acceptable salt thereof is usually 1 to 2000mg, preferably 20 to 500mg, for a human with a weight of 60 kg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner. The pharmaceutical composition or tablet of the present invention is generally administered orally, and for patients with difficulty in swallowing solid, the problem of administration can be solved by first disintegrating the tablet with water to form a suspension and then administering orally or nasally.
The pharmaceutical composition or tablet of the present invention may be administered alone or in combination with other therapeutic agents (e.g., hypoglycemic agents).
The pharmaceutical compositions or tablets of the invention may be combined with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug is maintained, while the pharmaceutical composition or tablet of the present invention is administered simultaneously or subsequently. The pharmaceutical combination also includes administering the pharmaceutical composition or tablet of the present invention in an overlapping time period with one or more other known drugs. When the pharmaceutical composition or tablet of the present invention is used in combination with one or more other drugs, the dosage of the pharmaceutical composition/tablet or known drug of the present invention may be lower than the dosage when they are administered alone.
Drugs or active ingredients that may be combined with the pharmaceutical composition or tablet of the present invention include, but are not limited to: estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, inhibitors of apoptosis, inhibitors of tumor growth, and the like, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and the like.
The main advantages of the invention are:
(1) the medicinal composition of the invention is easy to form, and can obtain the medicinal composition of the compound of the formula I or the pharmaceutically acceptable salt thereof in the form of tablets with uniform content and stable tablet weight by using a powder direct compression method.
(2) The medicinal composition has short disintegration time, high dissolution speed and very good chemical stability.
(3) The medicinal composition has the advantages of convenient processing, short sieving time, less phenomena of difficult tablet production, sticking and the like in the preparation process, and is very suitable for industrial production.
(4) The medicinal composition and the medicinal tablet further prepared from the medicinal composition still have good dissolution performance after long-term storage.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Test example 1 flowability study of the Compound of formula I
The flowability of the compound of formula I starting material was examined using a Brookfield engineering instrument and the Flow Function Graph (Flow Function Graph) shows that the flowability of the compound of formula I is cohesive (coherent) at low consolidation stress (coherent stress) and between cohesive (coherent) and easy flowing (easy flowing) at medium consolidation stress (coherent stress), indicating that the flowability of the compound of formula I starting material is poor.
When the compound of formula I is observed by an electron microscope, the compound of formula I is mostly in an irregular columnar structure, and a needle-shaped crystal structure is not generated, so that the crystal structure is not a cause of poor powder flowability.
Test example 2 chemical stability study of Compounds of formula I
Table 1 shows the results of the forced degradation of the bulk drug of the compound of formula I, which is stable at high temperature and under light conditions, relatively less stable under acid and base conditions, and easily degradable under oxidation conditions.
TABLE 1
| Item | Forced degradation conditions | Total miscellaneous | |
| Is not destroyed | Is not destroyed | 0.15％ | |
| | HCl | 60℃，3h | 2.37％ |
| | NaOH | 60℃，5h | 1.28％ |
| |
100℃，7h | 0.17％ | |
| Destruction by light | 6h | 0.16％ | |
| Oxidative destruction | 1％H2O2，1h | 5.35％ |
Test example 3 study of particle size variation of Compound of formula I by different treatment
The compound of formula I was processed by mechanical crushing and sieving, and the results are shown in table 2. It was found that the compound of formula I was very easily comminuted, mechanical comminution for 10 seconds giving a starting material particle size D90 of less than 30 μm.
TABLE 2
Comparative example 1
222.0g of compound of formula I, 22.0g of colloidal silicon dioxide, 863.5g of mannitol, 265.76g of microcrystalline cellulose, 44.0g of sodium stearyl fumarate, 51.26g of croscarmellose sodium and 61.6g of opadry film coating premixed powder are weighed, whether granules or caking phenomenon exists in the raw and auxiliary materials is checked during weighing, if yes, the raw and auxiliary materials are firstly sieved and weighed.
Firstly, mixing colloidal silicon dioxide, microcrystalline cellulose and croscarmellose sodium, and sieving; and sequentially adding the compound of the formula I and mannitol, uniformly mixing, adding sodium stearyl fumarate, and continuously and uniformly mixing to obtain intermediate powder.
And (4) detecting the content of the intermediate powder, calculating the weight of the tablet according to the content measurement result of the intermediate product after the intermediate powder is qualified, and pressing the tablet core. The tablet weight and hardness were monitored periodically during the compression process. For example, tablet cores of between 10mg and 240mg size may be compressed.
And (3) placing the qualified tablet core into a coating pot, taking a coating premix (Opadry 85F640013, and sampling 1.3-1.4 times of the theoretical tablet core weight increment of 3%), and preparing a coating suspension. And stopping coating after the weight of the tablet core is increased by 3-4%.
3 batches of 10mg standard tablets and 3 batches of 80mg standard tablets were prepared, and 6 tablets of each batch of 10mg and 80mg standard tablets obtained by the preparation were subjected to dissolution test (dissolution medium pH3.8, 75rpm), and as a result, as shown in fig. 1 and 2, dissolution in 30 minutes was 90% or more; however, the 6 tablets 80mg size tablets have a slightly lower dissolution for 30 minutes than the 6 tablets 10mg size tablets.
Comparative example 2
The dissolution rate of the tablet after stability lofting for 30 minutes was examined, including accelerated stability lofting (temperature 40 ℃. + -. 2 ℃ C., relative humidity 75% + -5%), and long-term stability lofting (temperature 25 ℃. + -. 2 ℃ C., relative humidity 60% + -10%). Table 3 shows the dissolution data after accelerated stability lofting (dissolution medium pH 3.8), and table 4 shows the dissolution data after long-term stability lofting (dissolution medium pH 3.8).
According to the data in tables 3 and 4, it can be found that the dissolution rate of the 80mg standard tablet is significantly reduced compared with that of the 10mg standard tablet after the sample is placed.
TABLE 3
TABLE 4
Comparative example 3
The tablets prepared in comparative example 1 were taken for various combinations to determine dissolution data (indicating that relevant samples had been stored under long-term stability-lofting conditions for about 15 months when the experiment was conducted); the average dissolution results are shown in table 5 (the average of 3 parallel experiments per group, expressed as cumulative percent dissolution); the data for group a, group B, group C, and group D are plotted in fig. 3. As can be seen from table 5, the average value of the total amount of dissolution showed a tendency to decrease as the tablet size increased.
Group a (10 mg): 10mg size 1 tablet (batch No. 160702) with a dissolution medium pH of 3.8.
Group B (80 mg): 80mg size 1 tablet (batch No. 160702) with a dissolution medium pH of 3.8.
Group C (120 mg): 10mg size 4 tablets (batch No. 160702) +80mg size 1 tablets (batch No. 160702), with a dissolution medium pH of 3.8.
Group D (400 mg): 80mg size 5 tablets (batch No. 160702) with a dissolution medium pH of 3.8.
Group E (400 mg): 80mg of 5 tablets (batch No. 160701) in a dissolution medium pH of 3.8.
Group F (400 mg): 80mg of the standard 5 tablets (batch No. 160701) and a dissolution medium pH of 2.0.
TABLE 5
| Time/minute | Group A | Group B | Group C | Group D | Group | Group F | |
| 5 | 89.10 | 84.83 | 67.06 | 58.00 | 57.23 | 101.46 | |
| 10 | 96.57 | 93.10 | 79.24 | 68.64 | 69.05 | 99.11 | |
| 20 | 96.97 | 95.40 | 83.96 | 75.51 | 75.47 | 98.56 | |
| 30 | 96.37 | 92.90 | 83.39 | 75.67 | 76.69 | 98.42 | |
| 45 | Not sampling | 93.37 | 83.78 | 78.15 | 77.32 | 98.79 | |
| 60 | Not sampling | 94.08 | 83.99 | 78.12 | 77.32 | 100.32 | |
| 90 | Not sampling | Not sampling | Not sampling | 78.35 | 76.86 | Not sampling | |
| 120 | Not sampling | Not sampling | Not sampling | 79.29 | 78.53 | Not sampling |
Comparative example 4 Wet granulation tableting method
Tablets were prepared by conventional wet granulation tableting according to the following formulation. The prescription is (w/w): 15.4% of compound shown in formula I, 47% of mannitol (added internally), 18.5% of microcrystalline cellulose (added internally), 5.4% of low-substituted hydroxypropyl cellulose (added internally), 1% of hydroxypropyl cellulose (prepared into 3% solution for granulation), 6.2% of microcrystalline cellulose (added externally), 4.3% of low-substituted hydroxypropyl cellulose (added externally) and 2.3% of sodium stearyl fumarate (added externally).
Compared with the examples, the wet granulation tabletting has good fluidity and high hardness; however, disintegration was slow, dissolution at 10 minutes was significantly less than powder direct compression, and dissolution at 10 minutes was only 7.6% (pH 4.5, 75 rpm).
Example 1
| Components | Ratio of (a)/% | 1 tablet content/mg |
| A compound of formula I | 25 | 80 |
| Lactose | 16.75 | 53.60 |
| Microcrystalline cellulose | 50.25 | 160.80 |
| Cross-linked polyvidone | 3.5 | 11.20 |
| Stearic acid sodium fumarate | 3 | 9.60 |
| Colloidal silica | 1.5 | 4.80 |
Weighing: compound of formula I, lactose, microcrystalline cellulose (PH302), crospovidone, sodium stearyl fumarate (S96), colloidal silicon dioxide, were accurately weighed on a 500 tablet scale.
Mixing: premixing other materials except the sodium stearyl fumarate, sieving for 3 times by a 40-mesh stainless steel sieve, adding the sodium stearyl fumarate into the sieved materials, mixing uniformly, taking 9 samples at different positions, and measuring the content uniformity.
Tabletting: calculating the weight of the standard tablet according to the content measurement result of the intermediate, controlling the weight of the tablet to +/-3%, controlling the hardness to be 90-120N, and tabletting.
Coating: the concentration of the prepared coating solution is 12%, and the weight of the coating is increased by 3-4%.
Example 2
| Components | Ratio of (a)/% | 1 tablet content/mg |
| A compound of formula I | 25 | 80 |
| Mannitol | 50.25 | 160.80 |
| Microcrystalline cellulose | 16.75 | 53.60 |
| Cross-linked polyvidone | 3.5 | 11.20 |
| Stearic acid sodium fumarate | 3 | 9.60 |
| Colloidal silica | 1.5 | 4.80 |
Weighing: the compound of formula I, mannitol, microcrystalline cellulose (PH302), crospovidone, sodium stearyl fumarate (S96), colloidal silicon dioxide were accurately weighed out on a 500-tablet scale.
Mixing: premixing other materials except the sodium stearyl fumarate, sieving for 3 times by a 40-mesh stainless steel sieve, adding the sodium stearyl fumarate into the sieved materials, uniformly mixing, and determining the content of the intermediate.
Tabletting: calculating the weight of the standard tablet according to the content measurement result of the intermediate, controlling the weight of the tablet to +/-3%, controlling the hardness to be 90-120N, and tabletting.
Coating: the concentration of the prepared coating solution is 12%, and the weight of the coating is increased by 3-4%.
Examples 3 to 6
Weighing: the compound of formula I, lactose, microcrystalline cellulose (PH302), crospovidone, sodium stearyl fumarate (S96) were accurately weighed on a scale of 1100 tablets.
Mixing: premixing other materials except the sodium stearyl fumarate, sieving for 3 times by a 40-mesh stainless steel sieve, adding the sodium stearyl fumarate into the sieved materials, uniformly mixing, and determining the content of the intermediate.
Tabletting: calculating the weight of the standard tablet according to the content measurement result of the intermediate, controlling the weight of the tablet to +/-3%, controlling the hardness to be 90-120N, and tabletting.
Coating: the concentration of the prepared coating solution is 12%, and the weight of the coating is increased by 3-4%.
For each example, 15 tablets were taken out and divided into 3 portions for dissolution test (dissolution medium pH 3.8). Samples were taken at 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes and the average cumulative percent dissolution was calculated. The dissolution rate test results are shown in Table 6 and FIG. 4.
TABLE 6
Example 7
| Components | Ratio of (a)/% | 1 tablet content/mg |
| A compound of formula I | 25 | 80 |
| Lactose | 52.50 | 168.00 |
| Microcrystalline cellulose | 17.50 | 56.00 |
| Low-substituted hydroxypropyl cellulose | 3 | 9.60 |
| Stearic acid sodium fumarate | 2 | 6.40 |
Weighing: the compound of formula I, lactose, microcrystalline cellulose (pH302), low-substituted hydroxypropylcellulose (L-HPC-B1), and sodium stearyl fumarate (S96) were weighed out on a 500-tablet scale.
Mixing: premixing other materials except the sodium stearyl fumarate, sieving for 3 times by a 40-mesh stainless steel sieve, adding the sodium stearyl fumarate into the sieved materials, uniformly mixing, and determining the content of the intermediate.
Tabletting: calculating the weight of the standard tablet according to the content measurement result of the intermediate, controlling the weight of the tablet to +/-3%, controlling the hardness to be 90-120N, and tabletting.
Coating: the concentration of the prepared coating solution is 12%, and the weight of the coating is increased by 3-4%.
Example 8
A formulation and method similar to example 4 was used (total amount of mannitol and microcrystalline cellulose per tablet was about 222mg, but weight ratios were as described above) using low-substituted hydroxypropylcellulose as disintegrant, mannitol as first filler, microcrystalline cellulose as second filler, and mannitol in a weight ratio of 7.6:1 to 1.8:1 as second filler. The preparation of the pharmaceutical composition by the powder direct compression method was similar to example 4 in terms of flowability, compressibility, disintegratability, and the like.
Example 9
Weighing: weighing the materials according to 80mg specification and 3500 tablet scale; 280g of the compound of the formula I, 583.8g of lactose (Flow100), 194.6g of microcrystalline cellulose (PH302), 39.2g of crospovidone (KCL), 22.4g of sodium stearyl fumarate (S96), 47.04g of Opadry film coating premix (85F640057) (weighing 140% of 33.6g of coating weight gain 3%, and 33.6g of loss in consideration of pipeline residue and the like); 344.96g of purified water was weighed.
Mixing: drymillu10 model multidirectional motion mixer, operating with a 5L mixing barrel. Sequentially adding microcrystalline cellulose, lactose and the compound of the formula I into a mixing barrel, and mixing for 15min at the rotating speed of 15 rpm; adding the crospovidone KCL into a mixing barrel, and mixing at the rotating speed of 15rpm for 15 min. 44.8g of the mixed material (2 times of the amount of the sodium stearyl fumarate) is weighed, mixed with sodium stearyl fumarate, sieved by a 40-mesh sieve, and then added into a mixing barrel to be mixed for 10 min.
Tabletting: a DPMODP020 type tablet press is selected from 10mm round punches. The weight of the tablet is 320mg, the hardness is controlled to be 105.00N +/-15.00N, and the tablet is prepared.
Coating: SOLID LAB 02 high-efficiency coating machine, 2.5L coating pan. Slowly adding the film coating premix into purified water to prepare coating liquid with the solid content of 12%. Stopping coating after the coating weight gain reaches 3.0% +/-1%.
The prepared coated tablets were taken for dissolution examination. Samples were taken at 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes and the average cumulative percent dissolution was calculated. The dissolution rate results are shown in Table 7. For each dissolution medium, 15 coated tablets were divided into 3 parts.
TABLE 7
Example 10
The samples prepared in example 9 were taken and simulated packed with High Density Polyethylene (HDPE) and heavy cold aluminium respectively, and after packing, the content and the change of related substances were examined in accelerated stability lofting (temperature 40 ℃. + -. 2 ℃ C., relative humidity 75%. + -. 5%), and the results are shown in Table 8.
TABLE 8
Example 11
Samples from the accelerated stability samples of example 10 (HDPE simulated packages) were sampled and tested for dissolution (0 day, 18 days, 2 months) and 15 tablets were taken each time and divided into 3 portions for dissolution testing (dissolution medium pH 3.8). The average cumulative dissolution percentage reached 93.95% (0 days), 93.22% (18 days), 97.95% (2 months) at 30 minutes.
Example 12
5 tablets of 80mg size prepared in example 9 were withdrawn and disintegrated into suspensions with 50mL of water, respectively, and rapid disintegration was observed (all samples disintegrated in 3 minutes). The dissolution of the suspension after disintegration is measured, and the result shows that the dissolution of the suspension after disintegration is slightly faster than that of the same tablet in the initial 5 minutes under the normal dissolution condition, and the dissolution curves of the rest time points and the tablet are not different; f2 similarity factor was greater than 50 and dissolution behavior was consistent.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (11)
1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof,
characterized in that the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a disintegrant, prepared by a powder direct compression process;
the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;
the filler is a combination of a first filler and a second filler, the first filler is lactose, and the second filler is microcrystalline cellulose; the weight ratio of the first filler to the second filler is 9: 1-1: 9;
the lubricant is sodium stearyl fumarate;
the disintegrant is crospovidone;
the pharmaceutical composition is free of colloidal silica;
the weight ratio of the filler to the active ingredient is 99: 1-1: 9;
the weight ratio of the lubricant to the active ingredient is 1: 1-1: 200;
the weight ratio of the disintegrating agent to the active ingredient is 1: 1-1: 90.
2. The pharmaceutical composition of claim 1, wherein the weight ratio of the first filler to the second filler is 9:1 to 1: 3.
3. The pharmaceutical composition of claim 1, wherein the weight ratio of the filler to the active ingredient is 8:1 to 1: 1.
4. The pharmaceutical composition of claim 1, wherein the weight ratio of the filler to the active ingredient is from 4:1 to 2: 1.
5. The pharmaceutical composition of claim 1, wherein the weight ratio of the lubricant to the active ingredient is from 1:2 to 1: 50.
6. The pharmaceutical composition of claim 1, wherein the weight ratio of the lubricant to the active ingredient is from 1:5 to 1: 15.
7. The pharmaceutical composition of claim 1, wherein the weight ratio of the disintegrant to the active ingredient is from 1:1 to 1: 30.
8. The pharmaceutical composition of claim 1, wherein the weight ratio of the disintegrant to the active ingredient is from 1:2 to 1: 15.
9. A process for preparing a pharmaceutical composition according to any one of claims 1 to 8, wherein the process comprises:
(1) mixing active ingredient, filler, lubricant, and disintegrant to obtain intermediate powder;
(2) tabletting was performed according to tablet weight.
10. A pharmaceutical tablet comprising a core and a coating over the core, the core being a pharmaceutical composition according to any one of claims 1 to 8.
11. Use of the pharmaceutical composition of any one of claims 1 to 8, or the pharmaceutical tablet of claim 10, in the manufacture of a medicament for treating cancer in a patient.
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